Patent Grant
11986167
The present invention relates generally to the collection of human sweat for analytical evaluation and, more particularly, to systems and methods for real-time sweat sampling and analysis.
Sweat has become an emerging biosource for biomarker discovery to sustain or enhance human performance. Typically, single large bulk sweat samples are collected for later off-line analysis. While useful, this sampling strategy limits the time-resolution of often-lengthy collection events and the utility of identified markers.
Historically, the most widely used method for sweat collections involves a single sample, obtained via a “patch” or other device, collected over the course of an entire experiment, such as an exercise or sweat stimulation regime. Therefore, the sample collected is only representative of the mean analyte concentration over the experimental time. As a result, changes of analytes, e.g. ions and metabolites, over the time course of the experiment are lost.
Therefore, a need exists for a system and method for real-time sweat sampling and analysis to better elucidate any changes in properties of the sweat and/or analyte concentration that may occur during the course of an experiment.
While the invention will be described in connection with certain embodiments, it will be understood that the invention is not limited to these embodiments. To the contrary, this invention includes all alternatives, modifications, and equivalents as may be included within the spirit and scope of the present invention.
The present invention relates generally to the collection of human sweat for analytical evaluation and, more particularly, to systems and methods for continuous real-time sweat sampling and analysis. Several embodiments of the sweat collection and analysis system are described herein.
The first embodiment provides a continuous real-time sweat collection system comprising a sweat collecting device comprising a main body having two surfaces comprising a sweat-collecting surface and an opposing outwardly-oriented surface. The sweat-collecting surface has a concave configuration which defines a rim lying wholly within a common plane. The main body has an axial bore extending between the sweat-collecting surface and the outwardly-oriented surface. A length of sweat collector tubing has one end joined to the main body at the axial bore and a free end that extends outwardly from the outwardly-oriented surface of the main body. The free end of the sweat collector tubing is in fluid communication with the input or source of a detector or instrument such as a mass spectrometer.
The method of using the first embodiment of the sweat collection system comprises:
The second embodiment provides a continuous real-time sweat collection system which comprises a sweat collecting article and a sweat collector tube. The sweat collecting article comprises a thin, flexible, conformable, and impervious covering. The covering has two surfaces comprising a body-facing surface and an opposing outwardly-oriented surface. The covering comprises a central portion, edges that define a perimeter, and a perimeter portion surrounding the central portion. The central portion of the body-facing surface is free of adhesive. The perimeter portion has adhesive on the body-facing surface for adhering the covering to a person's skin and for forming a seal around the central portion.
In the second embodiment, the sweat collector tube has a first end, a second end, and a length that extends between the first and second ends. The first end of the sweat collector tube is positioned adjacent to the covering so that the central portion of the covering overlaps a first portion of the tube. A second portion of the tube extends outward beyond one edge of the central portion of the covering and is adjacent to and is joined to the adhesive on the perimeter portion of the covering. A third portion of the tube extends beyond an edge of the covering to the second end of the tube. The second end of the tube is free to be placed in fluid communication with an instrument for analyzing the sweat.
The method of using the second embodiment of the sweat collection system comprises:
In addition, in any of the embodiments described above, or in other embodiments, salt may be removed from the sweat before it is transported to an instrument for analyzing sweat. An example of such an embodiment is a continuous real-time sweat collection and analysis system comprising:
Additional objects, advantages, and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the present invention and, together with a general description of the invention given above, and the detailed description of the embodiments given below, serve to explain the principles of the present invention.
It should be understood that the appended drawings are not necessarily to scale, presenting a somewhat simplified representation of various features illustrative of the basic principles of the invention. The specific design features of the sequence of operations as disclosed herein, including, for example, specific dimensions, orientations, locations, and shapes of various illustrated components, will be determined in part by the particular intended application and use environment. Certain features of the illustrated embodiments have been enlarged or distorted relative to others to facilitate visualization and clear understanding. In particular, thin features may be thickened, for example, for clarity or illustration.
The present invention relates generally to the collection of human sweat for analytical evaluation and, more particularly, to systems and methods for continuous real-time sweat sampling and analysis.
The MEGADUCT® sweat collection device 10, as described in the aforementioned patents, comprises a solid body 12 having a concave means defined at a face thereof by a sweat-collecting surface 14 which gradually recedes from a rim lying wholly within a common plane. In
U.S. Pat. No. 4,542,751, Webster, et al. describes how the sample of sweat is obtained when using the MEGADUCT® sweat collection device after it is collected in the spiral tubing. The tubing 20 has to be disconnected from the axial bore 16. The sweat then has to be expelled from the tubing 20 into a testing vessel by inserting an elastomer bulb into one end of the tubing 20 and squeezing the bulb. As a result, all of the sweat collected in the tubing is mixed together in the testing vessel. Because of this, it is not possible to analyze samples of sweat obtained at different times during the collection period.
The term “continuous”, as used herein, refers to sampling and analysis that takes place on an uninterrupted basis from the time the analytical instrument is started and sweat is received by the instrument. It is also within the scope of the present invention, however, for the sweat collection and analysis systems and methods to be operated in a non-continuous manner by interrupting the sampling and analysis, if desired.
The term “real-time”, as used herein, refers to a process in which the analysis is taking place as the sweat is being collected, rather than a process that involves collecting and storing the sweat for later analysis. The analysis will occur without placing the sweat in a separate container prior to conducting the analysis. Instead, the sweat may be transported by a conduit or tube directly to an analytical instrument (or after it has been processed by removing salt from the same as described herein). The time period in which the analysis may occur may be less than or equal to any of the following time periods after the generation of the sweat being analyzed: 15, 10, 5, 3, 2, or 1 minutes.
The terms “tube” and “tubing” may be used interchangeably herein. The tubing referred to herein is typically flexible along its entire length, although it is possible for portions of the tubing that do not move or conform to the body of the test subject during use to be relatively rigid.
The first embodiment of the sweat collection system 30 comprises a sweat collecting device 32 comprising a main body 34 and a length of sweat collector tubing 36. The main body 34 has two surfaces comprising a sweat-collecting surface 38 and an opposing outwardly-oriented surface 40. The sweat-collecting surface 38 has a concave configuration which defines a rim lying wholly within a common plane. The main body 34 has an axial bore 42 extending between the sweat-collecting surface 38 and the outwardly-oriented surface 40. The axial bore 42 is covered by other components in
The sweat collector tubing (or “tube”) 36 should have a length and an inside diameter that permits the transport of sweat therethrough at a rate which is sufficient to provide the sweat to an instrument for analyzing the sweat on a continuous real-time basis, or approximately real-time basis. It may be desirable for the person from whom sweat is being collected to be positioned close to the instrument to ensure that there is minimal delay between the sweat collection and the analysis. In some cases, it may, for example, be desirable for the participant to be within about 0.5 meter of the instrument. The length of the tubing 36 may, therefore, be less than or equal to about 0.5, 0.6, or 0.7 meter, or more. The inside diameter of the tubing 36 can be any size that is a small enough to transport sweat under the body secretion pressure yet large enough to transport a sufficient amount of the sweat to the instrument for analysis on a real-time basis. The inside diameter of the tubing should also be sufficiently small that there is substantially no mixing of the sweat obtained at various times during the sweat collection process. The inside diameter of the tubing 36 may be less than 0.85 mm, or less than (or less than or equal to about) 0.8 mm or 0.75 mm. In one embodiment, the tubing 36 has an inside diameter of about 0.01 inch (about 0.25 mm). Thus, the inside diameter of the tubing 36 may range from about 0.01 inch (about 0.25 mm) or less (e.g., about 0.2 mm) up to 0.85 mm. The sweat collector tube 36 can comprise any suitable material including, but not limited to polyetheretherketone (PEEK) tubing.
The main body 34 of the device can have a support 44 joined thereto such as to the outwardly-oriented surface 40 of the same for supporting the sweat collector tubing 36 during the sweat collection activity. The support 44 can comprise any suitable member or structure. The support 44 shown in
The first embodiment of the sweat collection device 32 can be made by modifying a MEGADUCT® sweat collecting device by removing the sweat collector tubing that is provided. The main body 34 of the sweat collection device 32 may, thus, have any of the properties of the solid body of the MEGADUCT® device described above. The sweat collector tubing 20 that is supplied with the MEGADUCT® device has an inside diameter of about 0.86 mm (about 0.34 inches) according to the patents referenced above. While this is suitable for collecting and storing sweat, it is not suitable for transporting sweat therethrough at a rate which is sufficient to provide the sweat to an instrument for analyzing the sweat on a real-time basis. It is estimated that the MEGADUCT® tubing may require as much as one hour to transport a sufficient quantity of sweat for analysis. The sweat collector tubing can be replaced with the PEEK tubing described above.
The free second end 36B of the sweat collector tubing 36 is placed in fluid communication (directly, or indirectly) with the input (or source) 46A of a detector or instrument for analyzing sweat 46 as shown in
The covering 54 has two surfaces comprising a body-facing surface 58 and an opposing outwardly-oriented surface 60. The covering 54 comprises a central portion 62, edges that define a perimeter 64 of the central portion 62, and a perimeter portion 66 surrounding the central portion 62. The central portion 62 of the body-facing surface 58 is free of adhesive. The perimeter portion 66 has adhesive 68 on the body-facing surface 58 for adhering the covering 56 to a person's skin and for forming a seal around the central portion 62. The adhesive 68 substantially or completely surrounds the central portion 62 to keep the central portion 62 in sufficiently close contact with the wearer's skin so that it does not form a gap or bubble adjacent the wearer's skin and forms a seal to prevent sweat from leaving the area of the wearer's skin covered by the central portion 62, other than through the sweat collector tube 56.
As shown in
The first piece of flexible film material 80 has two surfaces comprising a body-facing surface 84 and an opposing outwardly-oriented surface 86, an area, and edges 88 that define a perimeter 90. The first piece of flexible film material 80 fits against the person's skin and entraps sweat between the person's skin and the body-facing surface 84 of the material. The first piece of flexible film 80 should be liquid and vapor impervious, non-porous, non-absorbent, and conformable. The first piece of flexible film 80 may be inextensible. The first piece of flexible film material 80 can comprise any suitable flexible film including polymeric films, such as polyethylene or polypropylene. It may be desirable for the film to comprise virgin, rather than recycled polymeric material, to minimize the presence of contaminants. The first piece of flexible film 80 can be of any size suitable for covering a portion of a person's skin from which sweat will be collected. The size can vary depending on the experiment. In one case, the first piece of flexible film 80 comprises a small piece of plastic film (e.g., between about 2.5-3 inches in length by about 1¼ inch in width).
The second piece of flexible film material 82 has two surfaces comprising a body-facing surface 94 with adhesive thereon and an opposing outwardly-oriented surface 96. The second piece of film material 82 with adhesive thereon is sized and configured to extend beyond all of the edges 88 of the first piece of film material 80. The second piece of flexible film 82 may be liquid impervious, non-absorbent, and conformable, and it may also be moisture vapor permeable and extensible under the forces associated with attaching the second piece of film 82 to a person's skin. The second piece of flexible film material 82 can comprise any suitable flexible film including polymeric films, such as virgin polyethylene or polypropylene. The body-facing surface 94 of the second piece of flexible film material 82 has an adhesive 102 thereon for adhering to the outwardly-oriented surface 86 of the first piece of film material 80 and a person's skin. The adhesive 102 should be suitable for removably attaching the second piece of film 82 to a person's skin. The second piece of film 82 with adhesive thereon can comprise a commercially available bandage material such as OPSITE® transparent waterproof film manufactured by Smith & Nephew, Inc. Advanced Wound Management of Ft. Worth, TX, U.S.A, or TEGADERM™ transparent medical dressing manufactured by 3M™ of St. Paul, MN, U.S.A.
The sweat collector tube 56 in the second embodiment has a first end 56A, a second end 56B, and a body having a length that extends between the first and second ends. The tubing 56 can be the same type and have the same properties as the tubing 36 used above with the first embodiment of the sweat collecting device 32. In the second embodiment, the first end 56A of the sweat collector tube 56 is positioned adjacent to the first piece of film material 80 so that the first piece of film material 80 overlaps a first portion of the tube 70. A second portion 72 of the tube 56 extends outward beyond one edge of the first piece of film 80 and is adjacent to, and is joined to a portion of the adhesive 102 on the second piece of film material 82. The portions of adhesive adjacent to the second portion 72 of the tube 56 may hold the second portion 72 of the tube 56 adjacent to the wearer's skin. A third portion 74 of the tube 56 extends beyond the second piece of film material 82 to the second end 56B of the tube. The second end 56B of the tube is free to join to (and/or to be in fluid communication with) an instrument for analyzing the sweat.
The method of using the second embodiment of the sweat collection system comprises attaching the sweat collection article over an area of the person's skin. The sweat collection article can be attached to any suitable portion of the person's body from which a sweat sample can be obtained. For example, the sweat collection article can be attached to the inside of a person's forearm.
The sweat collection article 52 can be pre-assembled and placed on the person's skin; or it can be assembled as it is placed on the person's skin. In either case, the relationship of the components will be the same. The following will describe assembly of the sweat collection article on the person's skin. The first end 56A of the tubing 56 is placed adjacent the area of the person's skin. Next, a small first piece of plastic film 80 is placed over the first end of the tube 56A so that the first piece of film 80 overlies the first end 56A of the sweat collector tubing 56. There may be a small space between the wearer's skin and the first piece of film 80 to prevent the skin from adhering to first piece of material 80. A second piece of film material 82 with adhesive thereon that is larger than the first piece of film 80 is then obtained. If the second piece of film 82 is in the form of an adhesive bandage, any protective covering on the adhesive is first removed. The second piece of film 82 is applied over the first piece of film 80 so that its edges extend outward from the edges of the small first piece of plastic film 80. The second piece of film material 82 comprises a first portion of adhesive that adheres to the outwardly-oriented surface 86 of the first piece of film material 80 and a second portion of adhesive that adheres to a person's skin. The first and second portions of adhesive on the body-facing surface 94 of the second piece of film 82 may be separated or contiguous. The sweat collector tubing 56 extends outward from under the first and second pieces of film material 80 and 82 to its second end 56B, while the second portion of adhesive adheres part of the tubing 56 to the wearer's skin. The second end 56B of the sweat collector tubing 56 is placed in fluid communication with an instrument for analyzing sweat, and sweat is collected from the person's skin using the sweat collection article wherein sweat travels into the sweat collector tubing 56 and then into the instrument.
The size of the first and second pieces of film 80 and 82 can be adjusted based on the use/type of exercise. The location of the first end 56A of the tubing 56 and the angle that the tubing 56 makes relative to the vertical direction may also be set depending on the type of exercise. For example, if the subject is walking or running on a treadmill, the tube 56 may be oriented downward, since their forearms will be oriented downward. If the subject is on an exercise bike, then their arm will be oriented more horizontally or even with their hand elevated above their elbow. In the latter case, the tubing 56 may be oriented generally horizontally. In either case, it is desirable to position the first end 56A of the tubing 56 at a location under the first piece of film 80 where sweat will most likely flow by gravity.
The second embodiment is utilized by asking participants to perform a sweat collection either through stimulation, heat acclimation, or exercise with the invention worn on a part of their body. It is not necessary to induce sweating through the use of iontophoretic transporting of drug molecules through the skin. The sweat collection article 52 can be placed on the wearer's skin first, and then the person can be instructed to engage in the specified activity. Alternatively, but less desirably, the person may be instructed to initiate the specified exercise, and before the person begins generating sweat, the sweat collection article 52 can be placed on the wearer's skin. As in the case of the first embodiment, it may be desirable for the participant to be positioned close to the instrument to ensure that there is minimal delay between the sweat collection and the analysis. It may, for example, be desirable for the participant to be within about 0.5 meter of the instrument.
The prior art MEGADUCT® device shown in
In some embodiments, as shown in
Suitable mechanisms for removing salt include, but are not limited to electrodialysis, micro dialysis, and ion concentration polarization. Such microfluidic devices 48 having an input port 48A and an output port 48B can be connected in-line between the sweat collecting device 32 or 52 and the instrument for analyzing sweat 46. Passing the sweat through such devices will not result in an appreciable time delay in the real-time analysis of the collected sweat because the sweat can flow through such devices relatively quickly. For instance, electrodialysis is a membrane separation technology in which the ionized species are allowed to pass through an ion-exchange membrane by means of an external applied electric field. Microdialysis is a minimally-invasive sampling technique that is typically used for continuous measurement of free, unbound analyte concentrations in the extracellular fluid of virtually any tissue. As a result, the device 48 will provide a real-time rate of the migration of sweat from the individual to the instrument for analyzing sweat 46 to facilitate quantitative determination of changes in analyte abundance over time.
Various alternative embodiments of the systems and methods for collecting sweat over a period of time are possible. It is understood that several of the aforementioned steps can be performed in any suitable order. For instance, the method may involve attaching the sweat collection device over a person's skin before or after sweating is induced. In addition, in the second embodiment, the sweat collection article can be assembled first and attached to the wearer's skin; or it can be assembled on the wearer's skin by placing the tube against the wearer's skin and then placing the covering on top of the tube. The free end of the sweat collector tubing may be placed in fluid communication with the input port of an instrument for analyzing sweat either before or after the sweat collection device is placed on a person's skin. In addition, although collection and analysis of sweat from humans is primarily of interest, the system and method of the present invention could be used with any other biological subject that is capable of producing and excreting sweat.
The systems and methods for real-time sweat sampling and analysis described herein can provide a number of advantages including, but not limited to the following. This sweat collecting device and sweat collection and analysis system and method provide for continuous real-time sweat sampling and analysis. The current MACRODUCT® and MEGADUCT® products are primarily used to collect and then later measure the concentration of sodium and chloride in the sweat of children suffering from cystic fibrosis. The systems and methods of the present invention can be used to detect a relatively unlimited number of different analytes in sweat as the sweat is generated and collected, and to monitor any changes in analytes that occur over the period of collection. In the methods of the present invention, sodium and chloride may be removed as contaminants so that the instrument is better able to detect lower quantities of the analytes of interest. Other advantages are listed throughout this description. It should be understood, however, that these advantages need not be required unless they are set forth in the appended claims.
There are numerous, non-limiting embodiments of the invention. All embodiments, even if they are only described as being “embodiments” of the invention, are intended to be non-limiting (that is, there may be other embodiments in addition to these), unless they are expressly described as limiting the scope of the invention. Any of the embodiments described herein can also be combined with any other embodiments in any manner to form still other embodiments.
The term “joined”, as used herein, encompasses configurations in which an element is directly secured to another element by affixing the element directly to the other element; configurations in which the element is indirectly secured to the other element by affixing the element to intermediate member(s) which in turn are affixed to the other element; and configurations in which one element is integral with another element, i.e., one element is essentially part of the other element. The term “joined” includes both those configurations in which an element is temporarily joined to another element, or in which an element is permanently joined to another element.
The disclosure of all patents, patent applications (and any patents which issue thereon, as well as any corresponding published foreign patent applications), and publications mentioned throughout this description are hereby incorporated by reference herein. It is expressly not admitted, however, that any of the documents incorporated by reference herein teach or disclose the present invention.
It should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification includes every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.
While the present invention has been illustrated by a description of one or more embodiments thereof and while these embodiments have been described in considerable detail, they are not intended to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. The invention in its broader aspects is therefore not limited to the specific details, representative apparatus and method, and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the scope of the general inventive concept.
This application is a division of application Ser. No. 17/329,252 filed May 25, 2021, which claims the benefit of and priority to Provisional Application Ser. No. 63/083,403, filed Sep. 25, 2020, which is expressly incorporated herein by reference.
The invention described herein may be manufactured and used by or for the Government of the United States for all governmental purposes without the payment of any royalty.
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| Number | Date | Country | |
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| 20230240668 A1 | Aug 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| 63083403 | Sep 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17329252 | May 2021 | US |
| Child | 18194630 | US |
